OBJECTIVE: To determine how FN18-CRM9 influences the alloimmune response to the donor. RESULTS Renal allografts were performed in rhesus monkeys using FN18-CRM9, a potent immunotoxin capable of depleting T cells to less than 1% of baseline levels in blood and lymph nodes, as a preparative agent. We reported previously that animals pretreated with FN18-CRM9 1 week before transplantation without further immunosuppression had prolonged graft survival time compared with control animals, and frequently became tolerant. We examined the alloimmune responses of recipient monkeys to the donor, including cytotoxic T lymphocyte precursor (CTLp) frequency, mixed lymphocyte response, and antidonor IgG response. CTLp frequencies declined significantly after FN18-CRM9 treatment and renal transplantation. The decline was initially nonspecific, as frequencies against third-party animals also declined. The decrease was maintained in 5 of 5 animals tested 6 months after transplant; however, unresponsiveness was limited to the CTL arm of the immune response as antidonor IgG was detected in 4 of 4 animals tested and the 5-day mixed lymphocyte response stimulation index and relative response did not significantly differ before and after transplant. In long-term survivors, we saw an increase in anti-third-party CTLp 1 month after grafting with third-party skin. We saw no change in antidonor CTLp frequency after grafting, indicating the development of a specific defect in the antidonor CTL response. FUTURE DIRECTIONS These data suggest that FN18-CRM9 treatment of rhesus monkeys allows the development of specific down-regulation of antidonor CTL activity in renal allograft recipients. KEY WORDS MHC, tolerance, transplantation